2-benzazepinylalkylamino-benzamide derivatives

ABSTRACT

Analgesic 1-(2-(3-(1,2,4,5-tetrahydro-3H,3-benzazepinyl)) alkyl)-1,2,3,4-tetrahydro-4-quinazolinones, 2-(2-(3-(1,2,4,5tetrahydro-3H,3-benzazepinyl)) alkylamino)benzamides and precursers therefor. Methods are disclosed for preparation of the named compounds. Data regarding symptomatology, analgesic activity, local anesthesia and narcotic antagonism are given. Representative compounds are 1-(2-(3-(1,2,4,5-tetrahydro-3H,3benzazepinyl)) ethyl) -2-phenyl-1,2,3,4-tetrahydro-4quinazolinone and 2-(2-(3-(1,2,4,5-tetrahydro-3H,3benzazepinyl))ethylamino)benzamide.

United States Patent Shetty Nov. 5, 1974 2-BENZAZEPINYLALKYLAMINO-BENZAMIDE DERIVATIVES Primary ExaminerAlton D. Rollins 75 Inventor: BolaVithal Shetty, Bombay, India F"m charles Feeny [73] Assignee: PennwaltCorporation, Philadelphia, [57] ABSTRACT Pa. Analgesic l-(2-[ 3-(l,2,4,5-tetrahydro-3H,3- [22] Fllfid: 1971 benzazepinyl)]alkyl)-l,2.3,4-tctrahydro-4- [21] APPL 199,368 quinazolinones,2-(2-[3-(l,2,4,5-tctrahydr0-3H.3-

benzazepiny])] alkylamino)benzamidcs and precursers Related ApphcatmnData therefor. Methods are disclosed for preparation of the [60]Continuation-impart of Ser. No. 108,618, Jan. 21. named compounds. Dataregarding symptomatology,

1971, abandoned, which is a division of analgesic activity, localanesthesia and narcotic antag- 691955, 20, 1967' 3,635,976 onism aregiven. Representative compounds are l-(2- ]3-(l,2,4,5-tetrahydro=3H,3-benzazepinyl)] ethyl) -2- 260/239 260/243 B,260/2475 phenyl-l,2,3,4-tetrahydro-4-quinazolinone and 2-(2- 260/2564 Q,260/268 BC, 260/293.59, 3 12 4 5 h d -3l-l 3 b i 1 424/244, 424/246,424/248, 424/251, 424/267 thylamino)benzamide [51] Int. CL. C0711 41/08,C07d 57/02, C07d 99/10 Field of Search 260/238 BB 1 Claim, N0 Drawingsg;BENZAZEPINYLALKYLAMINO-BENZAMIDE DERIVATIVES CROSS-REFERENCES Thisapplication is a continuation-in-part of applica- 5 COR wherein R is H,loweralkyl, hydroxy, loweralkoxy, halogen, amino, or substituted amino(e.g. NHCOCH NH- CHO);

A is (CH where n is 1-5, or a branched alkyl with three to five carbonatoms;

R is H, OH, loweralkoxy, halogen or loweralkyl;

R and R each is H, lower alkyl, heterocyclic, aryl, aryl substituted byNH OH, OCH;,, CH or Cl, aralkyl or aralkyl substituted by OH, NH;, OCHCH or Cl;

R and R can be joined together to form with the two position carbon atomto which they are attached to cycloaliphatic or heterocyclic ringpreferably having three to 10 carbon atoms, either of which rings may beunsubstituted or substitued, e.g. NH OH, OCH;,, CH

R is H, lower alkyl, phenyl; aryl substituted by OH, NH OCH CH or Cl, orarylalkyl substituted by OH, NH CH O, CH or Cl; R is H, loweralkyl,heterocyclic, aryl, aralkyl, substituted aralkyl (e.g. NH OH, OCH CHCl), substituted aryl (e.g. OH, OCH:,, NH CH C1), or

O REL,

R is OH, loweralkoxy, (e.g. OCH OCH -CH het- NH NH- loweralkyl, N=(disubstituted with loweralkyl), phenylamino, substituted arylamino(e.g. the aryl radical substituted by OH, NH OCH CH 'Cl) aralkylamino,substituted aralkylamino (e.g. the

aralkyl radical substituted by OH, NH OCH CH Cl), and pharmacologicallyacceptable acid addition salts of the above compounds.

The compounds of the present invention may be prepared by variousmethods which are known in principle. Two convenient methods areillustrated in the following diagram of a general synthetic route, theschematic and short hand representations of which are those known in theart and wherein R is H or lower alkyl; R'CHCH is A, and R" is R and/or RREDUCTION R"COXI[METHOD B] Typical examples of compounds of thisinvention are: 1-(2-[3-(1,2,4,5-tetrahydro-3H,3-benzazepinyl)]ethyl)-2-methyl-1,2,3,4-tetrahydro-4-quinazolinone; l-(2[3-(1,2,4,5-tetrahydro-3H,3-benzazepinyl)] ethyl- )-2-phenyl-1 ,2,3,4-tetrahydro-4-quinazolinone; 1-(2-[3-(l,2,4,5-tetrahydro-3H,3-benzazepinyl)] ethyl)-2-benzyll ,2,3,4-tetrahydro-4-quinazolinone; 6-Amino- 1 -(2-[ 3-(l,2,4,5-tetrahydro-3H,3- benzazepinyl ethyl)-l ,2,3 ,4-tetrahydro-4-quinazolinone; 7-Amino-l-(2-[3-(1,2,4,5-tetrahydro-3H,3- benzazepinylethyl)-1,2,3,4-tetrahydro-4- quinazolinone;

1-(2-[3-( l,2,4,5-tetrahydro-3H,3-benzazepinyl)]ethyl)-spiro-[cyclopentane-l,2'(1 H)-quinazolin]- 4(3'H)-one; V I

l-(2-[3-(7-Hydroxy-l ,2,'4,5-tetrahydro-3H,3- benzazepinyl)] ethyl)- l,2,3 ,4-tetrahydro-4- quinazolinone;l-(2-[3-(7-Methoxy-l,2,4,5-tetrahydro-3H,3- benzazepinyl ethyl)-l ,2,3,4-tetrahydro-4- quinazolinone;

6-amino- 1 2-[ 3-( l ,2,4,5-tetrahydro-3H,3- benzazepinyl)]ethyl)-2-phenyl l,2,3,4-tetrahydro-4- quinazolinone;1-(2-[3-(7-hydroxy-1,2,4,5-tetrahydro-3H,3- benzazepinyl)] vethyl)-2-phenyl-l ,2,3,4-tetrahydro-4- quinazolinone;

1-(2-[3-(7-methoxy-1 ,2,4,5-tetrahydro-3H,3- benzazepinyl)]ethyl)-2-phenyll ,2,3,4-tetrahydro-4- quinazolinone;

l-(2-[3-( l ,2,4,5-tetrahydro-3H,3-benzazepinyl)] ethyl)-l ,2,3,4-tetrahydro-quinazolinone;2-(p-aminophenyl)-1-(2-[3-(1,2,4,5-tetrahydro-3H,8- benzazepinyl)] ethyll ,2,3 ,4-tetrahydro-4- quinazolinone;

l-(2-[3-( l ,2,4,5-tetrahydro-3l-l,3-benzazepinyl)]ethyl)-6-hydroxy-2-phenyl-l ,2,3,4-tetrahydro-4- quinazolinone;

1-( 2-{ 3-( l ,2,4,5-tetrahydro-3H,3-benzazepinyl)]ethyl)-6-methoxy-2-phenyl-l ,2,3,4-tetrahydro-4- quinazolinone;

l -(2-[3-( 1,2,4,5-tetrahydro-3H,3-benzazepinyl)]'ethyl)-1methyl-spiro-[piperidine-4,2'(1'H)-quinazolin]- 4(3H)-one;

2-( 2-[ 3-( l ,2,4,5-tetrahydro-3H,3-benzazepinyl)] ethylamino)benzamide;

-amino-2-(2-[3-( l,2,4,5-tetrahydro-3H,3- benzazepinyl)] ethylamino)benzamide; 4-amino-2-(2-[3-(1,2,4,5-tetrahydro-3I-l,3-

benzazepinyl)] ethylamino) benzamide;

2-(2-[3-(7-hydroxy-l,2,4,5-tetrahydro-3H,3- benzazepinyl)] ethylamino)benzamide, 2-(2-[3-(7-methoxy-1,2,4,5-tetrahydro-3H,3- benzazepinyl)]ethylamino benzamide; 2'-(2-[3-(1,2,4,5-tetrahydro-3H,3-benzazepinyl)]ethylamino)-4-benzoylmorpholine, and

2'-(2-[3-( l ,2,4,5-tetrahydro-3H,3-benzazepinyl)]ethylamino)-l-benzoylpiperidine.

If desired the above described compounds may be transformed into theiracid addition salts, or quaternary ammonium salts by customary methods.For instance the acid addition salts may be obtained by dissolving thefree base in a suitable solvent and acidifying the solution with thedesired acid. Suitable pharmacolog- Preparation ofbenzazepinyl)]ethyl)-2-phenyl-l ,2,3,4-tetrahydro-4- ically effectiveacid addition salts include the sulfates, Y

hydrochlorides, phosphates, cyclohexyl sulfamates,

maleates, citrates, tartrates, succinates, ethane disulfonates, methanesulfonate, isethionates, and the resinates obtained by reactingthe aminegroup of the compound with a cation exchange resin such as a sulfonic,carboxylic, or phosphoric acid cation exchange resin.

To prepare a quaternary ammonium salt the free base is merely reactedwith a suitable quaternerizing agent, such as an alkyl halide, anaralkyl halide or dialkyl sulfate, preferably in the presence of aninert or ganic acid.

The following working examples further illustrate the invention.

EXAMPLE I Preparation of 2-(2-[3-(1,2,4,5-tetrahydro-3(H),3-benzazepinyl)] ethylamino) benzamide (762-344) Step 13-(2-Hydroxyethyl)-l,2,4,5-tetrahydro- 3(H),3-benzazepinel,2,4,5-Tetrahydro-3(H), 3-benzazepine (74.75 g), 30 ml ethylene oxide,and 225 ml dry dioxane were charged into a sealed pressure vessel andheated at for 5 hrs. Another 15 ml ethylene oxide was added and heatingcontinued for another 5 hrs. The solvent was removed on the rotovap andthe residue recrystallized from ether-hexane to give 68 g after 3 crops.The solid was dissolved in 600 ml warm ether, decanted from a smallamount of insoluble material and 400 ml hexane added to give 24.5 gproduct m. 8487 C. Concentration of the mother liquor gave another 52.5g of product.

Step 2 3-(2-chloroethyl)-l,2,4,5-tetrahydro-3(H),-

benzazepine hydrochloride (81.4 g) was added to a mixture of 38 gZ-aminobenzamide, 54 g anhydrous sodium acetate, and 150 ml water. Themixture was stirred at reflux for 24 hrs and left overnight at roomtemp. Conc NH OH was added to make the mixture alkaline and the mixturewas extracted with chloroform. The chloroform extract was washed withwater, dried, concentrated, and the residue recrystallized from absolutealcohol to give 38.5 solid, m. 117121 C. The mother liquid was acidifiedwith CH1 gas, the solid filtered, washed, dissolved in water and thesoln made alkaline with sodium hydroxide. The base was extracted withchloroform and recrystallized to give 17.65 g product. A total of 51.7 gproduct was recrystallized twice to give 37.6 g, m. 120123 C. plus asecond naw-.6. s.-

l-(2-[3-(1,2,4,5-tetrahydro-3(H),3-

quinazolinone hydrochloride (762353) A mixture of 20 g2-(2-[3-(1,2,4,5-tetrahydro- C H N Calcd 71.96 6.50 9.68 Found 7l.856.54 9.59

PHARMACOLOGICAL ACTIVITY OF COMPOUNDS OF THIS INVENTION The compounds ofthis invention, when administered to mice by various routes, have beenfound to possess effective analgesic activity. These compounds arecharacterized further by a very low to medium order of toxicity inexperimental animals and appear to be substantially non-addicting. Inaddition to the primary analgesic activity these compounds possess otherpharmacological effects of potential utility. Among these otherpharmacological properties is activity in the sciatic block testindicating use as a local anesthetic. Different lots of the compoundsprepared as disclosed have not been found to display significantdifferences.

Solutions of compound 762-344 in distilled water were used for all ofthe tests set forth in Table I. In the case of compound 76235 3, a 2percent suspension of soluble starch (Clearjel) in distilled water wasemployed as the vehicle for the HNSD and LD tests; in all other testsset forth in Table I for this compound, distilled water was used as thevehicle.

ANALGESIC ACTIVITY The writhing test described by Sigmund et al, Proc.Soc. Exp. Biol. and Med. 952729 (1957) has been applied in both rats andmice as an indication of analgesic activity. This method has beenreported to be of value in detecting activity of narcotic antagonistanalgesics which sometimes do not exhibit activity with use of otherconventional methods. The stimulus of intraperi- Compound 762344 showsby its HNSD that it is an effective pharmacological agent of relativelyhigh potency. In addition, it is indicated to be an effective analgesicby the PBQ subcutaneous test. Compound 762353 has a very low order oftoxicity and is indicated by both the oral and subcutaneous PBQ tests tobe an effective analgesic.

LOCAL ANESTHETIC ACTIVITY In the case of both compounds 762344 and762353, a lpercent aqueous solution was used in the tests for localanesthetic activity. The mice used in the sciatic block test (3 mice percompound) were placed in a holder with their hind limbs extended. Aquantity of 0.05 ml of the test compound was injected into the areasurrounding the sciatic nerve at the juncture of the two major legmuscles.

An effective local anesthetic causes a blockade of the nerves of thelower leg and foot causing the animal, when permitted to walk, to do soflatfooted, rather than its normal habit, up on its toes. Alternativelyan effective local anesthetic, by the sciatic block method, can causethe leg to be dragged by the animal when walking so long as effectivesciatic block persists. Toxic agents may effect the same apparentresults, but the blockade effected by toxic agents is irreversible.However, in contrast to toxic agents, an effective local anestheticpermits recovery of the use of the leg and foot after a period of time.

From Table I, it will be observed that 762344 gave a positive result inthe sciatic block test, indicating an effective local anestheticactivity. (Where a positive result is indicated in Table I (Pos.), itmeans that the blockade did take place and that the leg and footreturned to normal after a time.)

NARCOTIC ANTAGONISTS Certain compounds have the ability to antagonizethe activity of strong narcotic analgesics in animals, whereas whentested by conventional methods in mice and rats little or no analgesiccan be demonstrated. Some of these compounds have been shown to be veryeffective analgesics in man. The compounds of this invention were testedfor their ability to antagonize nartoneal injection ofphenylbenzoquinone results in a writhing syndrone characterized byperiodic twisting 9 analgeslcs olflylnorphonei a mrPhme f and stretchingof the body with extension of the hind w Whlch when admmlstered tocauses Pupll jegs Frequency of writhing has been Shown to be dilation.It has been demonstrated in our laboratory duced or prevented by prioradministration of narcotic thflt narcotlc antagonists l 9 reduce F1115 yand non-narcotic analgesics. A test compound is conresponse P fi F Y Ifadmlmstered W 9 to sidered to have analgesic properties if, by prioradminmorphone adlTllnlstratlon, Whereas narcotic agents istration, it isable to reduce significantly the number of Such as P P Q and f cause nochange or writhes from that obtained by a group receiving vehicle Causean c ease In the pupil size.

TABLE I [.P. H. P0. 5.0. Compound HNSDI LD PBQ PBQ Local AnesthesiaNarcotic Antagonism mg/kg mg/kg ED mg/kg ED2 mg/kg Sciatic Block 76234410 I00 6 P05. Neg. 762-353 300 84 -84 Neg. Neg.

HNSD Highest nun-symptomatic dose. Thu! dose which is the highest thatcan be administered without appearance of gross effects.

LD, Median Lethal Dose PBQ Phenylhenzoquinone writhing test foranalgesia LP. Intraperitoneal S.C. Subcutaneous alone. The dose ofcompound protecting 50 percent of the animals of determined andexpressed as the ED Ten animals are used at each dose level.

ED, Median Effective Dose ethylamino) benzamide.

1. 2-(2-(3-(1,2,4,5-TETRAHYDRO-3H,3-BENZAZEPINYL)) ETHYLAMINO)BENZAMIDE.